Imidazopyrimidine-based inhibitor of Leishmania proteasome identified to treat visceral leishmaniasis

INDICATION: Leishmaniasis

Cell culture, in vitro, mouse, rat and dog studies identified an imidazopyrimidine-based inhibitor of Leishmania proteasome that could help treat visceral leishmaniasis. Chemical synthesis and screening in L. donovani-infected cell-based growth assays of analogs of a previously identified inhibitor of Trypanosoma cruzi yielded an imidazopyrimidine-based compound (GSK3494245) that inhibited parasite growth with an EC₅₀ of 1.6 μM. In vitro, the compound inhibited the chymotrypsin activity of Leishmania proteasome with an IC₅₀ of 0.16 μM. In a mouse model of visceral leishmaniasis, the compound decreased parasite load in the blood with a potency comparable to Impavido miltefosine. In mice, rats and dogs, the compound had an oral bioavailability of 18%, 35% and 46%, respectively. Ongoing work by GlaxoSmithKline plc includes testing GSK3494245 in preclinical models of visceral leishmaniasis...